Background: Xp11.2 translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer, which mainly occurs in young patients. The prevalence of this disease is about 30% in pediatric RCC, but ∼1% in adult RCC cases. Patients with tRCC are refractory to standard therapies for clear cell RCC. Therefore, there is no efficient treatment for this type of kidney cancer. The tRCC harbors gene fusions involving the TFE3 transcription factor on chromosome X with several partner genes, leading to TFE3 elevation in the cell nucleus, but its function remains unclear. We have successfully established a cell line and patient-derived xenograft from a tRCC patient to develop rational therapeutic strategies and understand the tumor biology.

Methods: We have utilized a feeder layer containing a ROCK inhibitor to favorably generate a cell line, 277T, from a young tRCC patient. Also, we have implanted tumor samples from the patient subcutaneously into SCID mice to establish a patient-derived xenograft model, RP-R-07, and continuously maintain tumor growth in vivo. Cells were treated with different drugs, and then assessed by MTT assay and trypan blue staining for growth inhibition and cell death investigations. TFE3 expression in cells and tumors were detected by immunofluorescence and immunohistochemistry. The combined drug effects were determined by CalcuSyn analysis.

Results: Our preliminary results demonstrated that TFE3 is predominately expressing in the nucleus of 277T cells and RP-R-07 tumor model compared to other subtypes of RCC by immunofluorescence and immunohistochemistry, respectively. Further, we treated 277T cells with several cytotoxic drugs showing that the cells didn't respond to docetaxel, doxorubicin, rapamycin, or a PI3K-mTOR inhibitor, but were sensitive to the Hsp90 inhibitor AUY922, and the HDAC inhibitor LBH589. Moreover, combining both AUY922 and LBH589 induced greater cell death compared to each single treatment (73% vs 41% for LBH589; 73% vs 19% for AUY922). In addition, an in vivo experiment indicated that LBH589 did inhibit tumor growth.

Conclusions: Overall our results indicate that tRCC is sensitive to HSP90 and HDAC inhibitors both in vitro and in vivo. The combination of LBH589 and AUY922 represents a promising strategy for treating tRCC

Citation Format: Sheng-Yu Ku, Swathi Ramakrishnan, Eric Ciamporcero, Bo Xu, Gissou Azabdaftari, Richard Cheney, Roberto Pili. HDAC and Hsp90 inhibition as therapeutic strategy for translocation renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2546. doi:10.1158/1538-7445.AM2015-2546

©2015 American Association for Cancer Research.
2015